Podocyte foot processes (FPs) and the interposed slit diaphragm (SD) form the final barrier to protein loss, explaining why podocyte injury is typically associated with marked proteinuria. Podocyte dysfunction, represented by FP effacement, disruption of the SD and proteinuria, is often the starting point for progressive kidney disease. Here we propose to test our central hypothesis that the induction of hic-5 expression in podocytes contributes to the pathogenesis of proteinuria by increasing the adhesiveness of podocyte to the extracellular matrix (ECM)/glomerular basement membrane (GBM). We further hypothesize that the persistence of podocyte hic-5 expression in focal segmental glomerulosclerosis (FSGS) confers a senescence phenotype, thereby promoting the progression to ESRD. To test this hypothesis, we propose three Specific Aims. The first Aim will define the molecular mechanism whereby hic-5 increases podocyte adhesion to the ECM, thereby altering cell motility, survival and senescence. Specific Aim two seeks to test whether the induction of podocyte-specific hic-5 expression in mice causes proteinuria. The third Aim will establish whether the prolonged expression of hic-5 in podocytes induces hypertrophy, senescence and apoptosis, thereby causing FSGS and progression to ESRD. If our hypothesis is correct, the work proposed here will have broad significance because it will provide us with a better understanding of the biological mechanism underlying the development of progressive proteinuric kidney diseases and offers a new target for the development of treatment strategies. This should in the long- term enable us to develop novel, podocyte-protective therapies that tackle proteinuric kidney diseases by suppressing the hic-5 mediated increased adhesion of podocytes to the GBM. Such hic-5 blocking compounds may also slow the progression of FSGS to ESRD by inhibiting the hic-5 mediated senescence of podocytes. PUBLIC HEALTH RELEVANCE: Our novel preliminary data, described in this grant application, identified a hic-5- dependent signaling pathway that contributes to the pathogenesis and progression of proteinuric kidney diseases by modulation podocyte adhesion to the extracellular matrix/glomerular basement membrane. The goal of this application is to define the molecular mechanisms whereby the modulation of hic-5 expression in podocytes causes proteinuria, thereby paving the road for the development of novel anti-proteinuric treatment options for which there is a critical need in the clinic.